title: A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis.
abstract: Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25  ml/min per 1.73  m(2), and a urine protein to creatinine ratio over 1.8  mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4  mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73  m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2  mg/mg with all three Black patients having a mean decline of 3.6  mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.
authors.affiliation: Division of Nephrology, Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA. trachtma@lij.edu
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Fervenza
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Gipson
authors.forename: Peter
authors.initials: P
authors.lastname: Heering
authors.forename: David R W
authors.initials: DR
authors.lastname: Jayne
authors.forename: Harm
authors.initials: H
authors.lastname: Peters
authors.forename: Stefano
authors.initials: S
authors.lastname: Rota
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: L Christian
authors.initials: LC
authors.lastname: Rump
authors.forename: Lorenz K
authors.initials: LK
authors.lastname: Sellin
authors.forename: Jeremy P W
authors.initials: JP
authors.lastname: Heaton
authors.forename: James B
authors.initials: JB
authors.lastname: Streisand
authors.forename: Marjie L
authors.initials: ML
authors.lastname: Hard
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.forename: Flavio
authors.initials: F
authors.lastname: Vincenti
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000652:urine; D001706:Biopsy; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007263:Infusions, Parenteral; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D016212:Transforming Growth Factor beta; C560928:fresolimumab; D003404:Creatinine